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3. Gut Microbes:
How They Help us OutStephanie Senef Wise Traditions Workshop
Nov. 8, 2013
eople.csail.mit.edu/senef/W!"#Slides#2013/3#$ut#%acteri
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Outline
• 'ut %acteria under sie$e
• (n&ection) novel perspective
•
(n*uen+a• Natural resistance and anti%iotics
• Summar
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'ut -acteria nder Sie$e
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Gut Bacteria and Health*
• We are an ecosstem) a communit o&
interactin$ cells – Trillions o& %acteria live in our %od
– The outnum%er our on cells 10)1
– illin$ them of ma make us sick or &at
•
8 million micro%ial $enes in our %odies3 million in di$estive sstem&rom more than1000 species4
• The pla ver essential roles in our %odies
– 5i$est &oods, a%sor% nutrients, provideen+mes, make vitamins and
antiin*ammatories
– 6e$ulate appetite and %rain &unction
• 7a$inal %irth mattersN!6;s /20/%ac
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“Our microbes are under threat— and the enemy is us*
•
?@icro%iomeA – BBC o& them are %eni$n or ofer protection
– Snthesi+e vitamins -12 and &olate
• -irth throu$h %irth canal v.s. D section4 –
(n&ant picks up motherEs micro%iome• Dolostrum provides &ood &or $ut %acteria
• (ndustriali+ed countries are too clean – 5rasticall altered micro%iome
• F. plori B0C G 10C in last hundred ears in .S.• sopha$eal cancer and childhood asthma have risen
in step
S+a%o, S Toda,/.usatoda.com/nes/health/stor/20120I13/%od%u$smicro%es/>2B
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H. pylori: There areBene!ts"*
• The Western orld has no si$niKcantlreduced the presence o& F. plori in the $ut – This has reduced the incidence o& stomach ulcers
and stomach cancer
– -ut it has also increased the incidence o&esopha$eal re*uL disease and esopha$eal cancer
• F. plori serve a use&ul role in reducin$ acidproduction % stomach) eLcess acida$$ravates the esopha$us
• We host a colon o& %acteria and the orkto$ether ith us &or a Mointl %eneKcial solution
:Daroline Fadle, @-< reports 7(5), 471-473, 2
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?
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Glyphosate and the #hi$imate%athway*
• 'lphosate disrupts the shikimatepatha, leadin$ to ds%iosis o&aromatic amino acids
•
@onsanto claims $lphosate issa&e %ecause human cells don;thave the shikimate patha
• Foever, $ut %acteria are ver important to
human health, and the do have the patha• 5s%iosis in the $ut is increasin$l %ein$
reco$ni+ed as a &actor in modern diseases
-
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Glyphosate and the #hi$imate%athway*
• 'lphosate disrupts the shikimatepatha, leadin$ to ds%iosis o&aromatic amino acids
•
@onsanto claims $lphosate issa&e %ecause human cells don;thave the shikimate patha
• Foever, $ut %acteria are ver important to
human health, and the do have the patha• 5s%iosis in the $ut is increasin$l %ein$
reco$ni+ed as a &actor in modern diseases
( ill have much moreto sa a%out this in
the section on$lphosate
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&eliac 'isease: an(pidemic*
• Deliac disease $luten intolerance4 is &oundthrou$hout the S at a rate o& up to 1 inever 133 persons, several orders o&
ma$nitude hi$her than previouslestimated
•
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?Time and time a$ain, e hear &rompatients that the never &elt depressedor anLious until the started
eLperiencin$ pro%lems ith their $ut.1I.asp
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&onnections Between the Gut andthe Brain*
.". Dran and T.'. 5inan, Nature 6evies Neuroscience 2012, I01I12.
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)ecapitulation
• Fealth $ut %acteria are essential to health
• 'lphosate 6oundup4 disrupts $ut %acteria
•
Deliac disease is a modern epidemic, likeldue to $lphosate more later4
• F. plori has %oth pros and cons
• The $ut%rain aLis links $ut %acterial
distress to neurolo$ical diseases
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(n&ection) Novel !erspective
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n+ection
(mpaired cholesterol sul&ate snthesis canlead to suscepti%ilit to in&ection, hich
introduces idespread patholo$
(n&ection serves a use&ul role inresupplin$ critical nutrients such as
co%alamin, &olate, and heparan sul&ate
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,ea$y Gut #yndrome*
: "rom http)//.precisionnutrition.com/alla%out$luten
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-ild #peculation
• Heak $ut and leak skin andleak %lood %rain %arrier lead
to inKltration o& micro%es&rom $ut or skin into %rain
• -acteria are ?luredA into the%od P into the %rain and
then killed and harvested torene important
nutrients• !ossi%le nutrients include)
– 7itamin -12 co%alamin4, vitamin -B &olate4,thiamine, vitamin and heparan sul&ate
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a auses ncreasen+ection
(mpaired Dholesterol Sul&ate SnthesisQ
@icro%es
@icro%es
@icro%es
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/drenalin #timulates BacterialGrowth*
• 7arious species $ron in culture%oth $ram ne$ative and $rampositive4
• drenalin added to mediumstimulated $roth
• Some species produce unknon
$rothenhancin$ stimulus inpresence o& adrenalin
– This can stimulate $roth o& other
species as ell:.S. inne et al., Hi&e Sciences >I 20004 30I
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#ul+ate 'epletion in&olitis *
• ''s in intestinal mucosa $reatl depleted insul&ate in association ith %oth colitis andDrohn;s disease – Dolitis) mostl ''s in luminal sur&ace
– Drohn;s) mostl ''s near %lood vessels
• Serum al%umin leaves vasculature andpenetrates intestinal linin$) – (nsuRcient ne$ative char$e results in eas access
• Serum al%umin depletion has severeconse9uences to %lood sta%ilit
: @urch et al., The Hancet 3J1)I11I1J, @ar 20, 1BB3
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#ul+ate 'epletion in&olitis *
• ''s in intestinal mucosa $reatl depleted insul&ate in association ith %oth colitis andDrohn;s disease – Dolitis) mostl ''s in luminal sur&ace
– Drohn;s) mostl ''s near %lood vessels
• Serum al%umin leaves vasculature andpenetrates intestinal linin$) – (nsuRcient ne$ative char$e results in eas access
• Serum al%umin depletion has severeconse9uences to %lood sta%ilit
: @urch et al., The Hancet 3J1)I11I1J, @ar 20, 1BB3
!eople ith colitis or Drohn;shave $reatl increased risk to
colon cancer
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,ea$y Gut
• 6educed sul&ate in the ''s in theintestines
• Dells are de&ective in transportin$ nutrients – Heads to severe vitamin deKciencies e.$., -124
• Ti$ht Munctions %eteen cells %ecome loose
• @icro%es can penetrate the $ut all andenter the %lood stream
– The can %e harvested % macropha$esQ
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Micro0illi in Gall Bladder(pithelium*
Fealth ne$ative char$e makes them stand tall
nhealth addition o& cationic polmer destros them
res 1 and 2 in uinton and !hilpott, O. Dell -iol. >, 1BI8, I
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Bacteria can #wim /cross GutBarrier"
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Microbial n0asionthrou1h BBB*
: "i$ure , p. 380, O..
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The Good #ide o+ n+ection andn2ammation in the Brain
• (n*ammation activates micro$lia topha$octose eat4 din$ cells andmloid %eta
• -acterial eLposure promotespha$octosis
• Both dying cells and acteria can e
recycled into ne! ra! "aterials# – $hese n%trients "ay e essential to rain
health
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/ %ossible &auseand(4ect)elationship
• "irst comes impaired %arriers, impairednutrient transport and impaired %loodcolloidal suspension
• Dertain nutrients are desperatel neededto KL the pro%lems) e.$., co%alamin,vitamin , heparan sul&ate – -acteria are invited in to provide those
nutrientsQ
• The disease ma %e uncom&orta%le, %utthe alternative ma %e orseQ
n+ection and
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: . Tu&ano et al., Semin Throm% Femost 2012384, 1
n+ection and/therosclerosis*
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-hat Happens i+ you Treatwith /ntibiotics*
. Tu&ano et al., Seminars in Throm%osis P Femostasis7ol. 384, 2012, 123
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-hat Happens i+ you Treatwith /ntibiotics*
. Tu&ano et al., Seminars in Throm%osis P Femostasis7ol. 384, 2012, 123
Si$niKcantl more people die o&cardiovascular disease &olloin$
anti%iotic treatment p0.014
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&hlamydia pneumoniae
• Dause pneumonia henthe in&ect the lun$s
• Sho up &re9uentl in
cardiovascular pla9ue• Sho up &re9uentl in
l+heimer;s pla9ue
&hat are they doing there'''
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&hlamydia %roduce Heparan#ul+ate"*
• Dhlamdia are via%le onlinside host cells
• The set up housekeepin$
in vacuoles ithin the celle.$., a macropha$e in the
pla9ue4
•
The produce a $lucosaminecontainin$sulphated polsaccharide that is nearlindistin$uisha%le &rom heparan sul&ate
• The have a uni9ue set o& en+mes &or this: S.O. 6asmussenHathrop et al, Dell @icro%iol. 2000 pr, 224, 13IJJ
# i l ' t d t /l h i 6
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#pecial ssue 'e0oted to /l5heimer6sand n+ection:* 7ey %oints
•
!atho$ens can produce pro$ressive chronic diseaseslike l+heimer;s, asthma, and heart disease
• l+heimer himsel& proposed involvement o& in&ectivea$ents in l+heimerEs 100 ears a$o
• !atho$ens stimulate in*ammation
• !atho$ens evade host de&enses and esta%lish chroniclatent in&ections
• !ersistent superoLide, nitric oLide and peroLnitrite6
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/myloid %la8ue #tructure*
• @icro$lia and amloid pla9ueaccumulate side%side in acentral re$ion surrounded %astroctes
• @icro$lia har%or dormant%acteria
• Should the %acteria leave,the ill encounter the
pla9ue, hich ill kill them• The astroctes $uard the
$ates and shield the neurons&rom the dama$in$ pla9ue : @icrophoto$raph &rom
Scha% et al., Oournal o&
l+heimer;s 5isease 13 3B
Dhlamdia in pla9uere$ion produceheparan sul&ateQ
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#epsis and the9asculature*
(mmune cellsstick to all o&
venule and%lock *o
Small %loodclots &orm in
capillaries and%lock *o
. Tr+eciak et al., cad mer$ @ed. 2008 @a U 14) 3BBJ
(mpaired a%ilit tomodulate %lood
*o
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(4ect o+ deno0o statin treatment onpatients with sepsis plus pneumonia*
Haurent !apa+ian et al., O@,
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Hypothesis
-lood *o needs to nearl shut dondurin$ sepsisU or$ans need to shut donU
the entire %od &ocuses on harvestin$heparan sul&ate &rom the invasivemicro%es to recover %lood sta%ilit.
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)ecapitulation
• (n&ection is a conse9uence o& impaired suppl o&sul&ate to the %arriers
• Heak $ut sndrome allos %acteria to personalldeliver nutrients to the %od
• drenalin encoura$es %acterial $roth to helpsuppl nutrients under stressX4
• therosclerosis is associated ith in&ective a$ents,%ut anti%iotics make thin$s orse
•
Dhlamdia pneumoniae can produce heparan sul&ateusin$ a uni9ue set o& en+mes – 5o the help us out in pneumonia, heart disease and
l+heimerEsX
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(n*uen+a
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n2uen5a
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lu 9accine ncreases )is$ toOther )espiratory n+ections*
:-O Dolin$ et al., D(5 2012)J, 1I
•
5ou%le%lind randomi+edtrial conducted in Fon$ on$
• 11 children a$ed >1 ears –
6eceived 2008200B seasonal trivalentin*uen+a inactivated vaccineT(74 or place%o
– @onitored over &olloin$ B months
• T(7 recipients did not have asi$niKcant reduction in risk to *u
• T(7 recipients had a 44-old
increased risk to nonin*uen+a
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#upplement and 'ietary%rotection +rom n2uen5a*
• Nacetlcsteine
• 'reen teacatechines4
:S. 5e "lora et al., ur 6espir O 10 I4) 131J1.
M l / h d % i
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Muscle /ches and %ainswith lu*
?!atients ith an in*uen+alike illnessshould %e o%served &or si$ns andsmptoms o& rha%domolsis and
mo$lo%inuria durin$ the course o& theirillnessA
.s the ir%s leaching s%latero" the "%scles'
:6 @ino et al., nn (ntern @ed. 1BIJU8034)3B
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'oes n2uen5a 9irusTransport #ul+ate
• (n*uen+a virus – (n&ects muscle cells and causes muscle astin$:
– (ncorporates sul&ated mucopolsaccharidessnthesi+ed % the host cell into its on plasma
mem%rane:: – (nhi%its mucopolsaccharide incorporation into the
host cellEs mem%rane.::
.s iral inection an opport%nity to steal s%latero" "%scle cells and delier it to the lood'
: F essler et al., O@ 1B80 2J34, J>1J>2.::Nakamura and Dompans, 7irolo$ IB24, 1BII, 3813
Thi T M
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s This True MoreGenerally*
:-ernhard @uschlien, (n*ammations and Their Therap %@eans o& (so ath
copolsaccharides la%elled ith radioactive sul&ur to measure $roth
(n&ected animals
@ore sul&ur shoed up inmultiple tissues &olloin$in&ection
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&holine sul+ate""*
• !roduced % plants, lichens, al$ae,&un$i, and several %acterial species
• Lperiment demonstrated that it had
superior capa%ilities to inhi%it amloid&ormation in pancreatic %eta cells – mloid in %eta cells is
akin to amloid %eta in
l+heimerYs disease andplas a maMor role in tpe((
dia%etes
:@. Fa$ihara et al., "-S
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Tami*u and deLtran sul&ate are dru$s to suppress*u virus replication that are imitations o&
products produced % $ut %acteria
u s a t reat
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:http)//articles.mercola.com/sites/articles/archive/2012/02/0Irecommendedtami*uhas*aedresults.as
u s a t reat and Tami2u is the
answer*Side efects include) – Donvulsions, delirium and delusions
–
ller$ic reactions includin$ anaphlaLis – Fepatitis and elevated liver en+mes
– Nausea, diarrhea
– Ni$htmares
– Feadache
– Skin rash
>euraminic /cid and
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>euraminic /cid andTami2u
• Neuraminic cid) -asic unitin sialic acids
in human''s
• -roken don % ne%ra"inidase produced % *u virus
• $a"i/% inactivates neuraminidase –
This prevents viral entr into cell – Shikimate is a precursor to active in$redient in Tami*u
– Shikimate is produced % $ut %acteria
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nhibition o+ >euraminidase by'e?tran #ul+ate*
• Ne$ativel char$ed, sul&atedpolsaccharide – Snthesi+ed &rom sucrose % lacticacid
%acteria – Suppresses replication o& in*uen+a
virus strain
– (nduces viral a$$re$ation at cell sur&ace
– (nhi%its neuraminidase activit likeldue to its ne$ative char$e4
– sed as dru$ to treat *u
:F =amada et al., ntiviral 6es. 2012 5ecUB>34)3JJ
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nhibition o+ >euraminidase by'e?tran #ul+ate*
• Ne$ativel char$ed, sul&atedpolsaccharide – Snthesi+ed &rom sucrose % lacticacid
%acteria – Suppresses replication o& in*uen+a
virus strain
– (nduces viral a$$re$ation at cell sur&ace
– (nhi%its neuraminidase activit likeldue to its ne$ative char$e4
– sed as dru$ to treat *u
:F =amada et al., ntiviral 6es. 2012 5ecUB>34)3JJ
%acterium that inter&eres ith *u virus
can transport the deLtran sul&ate todistant places.
5eLtran sul&ate as a dru$ is a ?trickA.
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'e?tran #ul+ate
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-7 on 'e?tran
The antithrom%otic efect o&deLtran is mediated throu$h its%indin$ o& red %lood cells,platelets, and the endothelial cellsin the vascular all, increasin$their electronegatiity and thusreducin$ red %lood cell aggregation and platelet adhesieness.
#id (4 + ' # l+
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#ide (4ects +rom 'e?tran #ul+ateTreatment
• naphlaLis itch rash, throatsellin$, and lo %lood pressure4
• Lcess *uid in %lood
• !ulmonar edema
• Dere%ral edema
• !latelet ds&unction
The molecule %itsel& can;tmultipl
hereas%acteria thatproduce it canQQ
%hase Trial: Hepatitis &
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%hase Trial: Hepatitis &'ru1*
• Trial halted earl due to B hospitali+ations and1 death – 5ru$ orks % thartin$ viral replication machiner
– 5ru$ is toLic to heart and kidne
• Side efects o& hepatitis D treatments, more$enerall, include anemia, cardiacarrhthmias, severe depression, and *ulikesmptoms
• Dholesterol sul&ate is a natural inhi%itor o&Fepatitis D::
)//.thescientist.com/Xarticles.vie/articleNo/322/title/DlinicalTrial@is&o
uruta et al., O n+me (nhi% @ed Dhem. 2013 "e% 2. Vpu% ahead o& print
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)ecapitulation
• -etter to prevent *u than to treat it
• -etter to prevent *u throu$h nutrition thanthrou$h vaccines
• "lu is associated ith achin$ muscles) is thevirus &orcin$ muscles to $ive up their sul&ateX
• Treatin$ *u can lead to severe ?side efectsA – re these the conse9uence o& the virus %ein$
a%orted earl %e&ore it can &ollo throu$h on itspromise to deliver sul&ate to the %lood streamX
• ( suspect man other viruses e.$., hepatitis D4provide muchneeded sul&ate to the %od
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Natural 6esistance and nti%iotics
Multiple /ntibiotic
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Multiple /ntibiotic)esistance
• nti%iotic resistance is a serious and$roin$ threat in modern times
•
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,', %rotects +rom M)#/*
eterson et al., Dell Fost @icro%e J>4) >>, 2008
•
@ethicillinresistant Staphlococcusaureus @6S4 has %ecome amaMor pro%lem inhospitals orldide
• po- in H5H limits invasion % %indin$to and neutrali+in$ a ke
en+me responsi%le &orpromotin$ invasion throu$h
the skin
• Skin penetration and %acterial densit eresi$niKcantl $reater in po-deKcient mice.
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Th M)#/ ( id i *
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The M)#/ (pidemic*
:@. -erens and . rmstron$
Fo our hospitals unleashed a @6S epidemic Seattle Times 111>, 2008
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M)#/ in &hildren On The )ise*
• The in&ections overhelmin$l resulted inhospitali+ation B1C4U >C ere &atal.
• @ost o& the afected kids >8C4 had anotherunderlin$ medical condition, most commonlprematurit 1BC4 or a skin condition such asec+ema or a%scesses 18C4.
• -lack children also had a disproportionate
share, accountin$ &or BC o& the cases, ithan incidence o& >.I versus 1.> per 100,000amon$ other children.
:Drstal !hend , @edpa$e Toda Sept. 23, 201
&lostridium 'i@cile and 7lebsiella
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%neumoniae /re &omin1*
:.Mon%arron.or$/topic/clostridiumdiRcileandkle%siellapneumoniaearec
• To super %u$s resistant to nearl all anti%iotics
• -reakouts in hospitals are dire threats• Suscepti%ilit
– Weakened immune sstem
– 5isrupted $ut %acteria
•
Dlostridium diRcile D. dif 4 – Spores are nearl indestructi%le
• Ne kid on the %lock) le%siella pneumonia superstrain –
6esistant to ever sin$le anti%iotic in the medical arsenal. – nclosed % a polysaccharide capsule that protects &rom
anti%iotics
– (nitiall *ulike smptoms
• hi$h &ever, chills, cou$h
• copious amounts o& viscous and %lood mucous in the
uoro8u nones: o? c/ tibi ti "*
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8/ntibiotics"*
• mon$ the most commonl prescri%ed anti%iotics in the
S – (nhi%it %acterial 5N snthesis
– "luoride increases penetration into ---
• Smptoms include) – Nervous sstem smptoms tin$lin$, num%ness, anLiet,
memor loss, pschosis ..4
– @usculoskeletal smptoms tendonitis, eakness, Mointsellin$ ...4
– Sensor smptoms tinnitis, altered vision, ...4
–Dardiovascular smptoms tachcardia, chest pain,palpitations ...4
– Skin reactions rashes, hair loss, seatin$ ...4
– 'astrointestinal smptoms nausea, vomitin$, diarrhea...4
icles.mercola.com/sites/articles/archive/2013/0B/2/*uoro9uinoloneanti%iotics.
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)ecapitulation
• @ultiple anti%iotic resistance is a$roin$ pro%lem – Dould it %e due to insuRcient cholesterol
and insuRcient sul&ateX• "i$htin$ disease ith anti%iotics (s a
losin$ proposition –
5ru$ resistant micro%es lead to evermore toLic anti%iotics
– Side efects o& the anti%iotics can kill ou
#ummary
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#ummary•